rs139365610

Variant names:

• chr19-49807348-C-A
• rs139365610
• NM_025129.5:c.1060G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-49807348-C-A
• chr19-49807348-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_025129.5(FUZ):​c.1060G>T​(p.Asp354Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D354N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: FUZ NM_025129.5 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 2.02
• Publications: 8 publications found

Genes affected

FUZ (HGNC:26219): (fuzzy planar cell polarity protein) This gene encodes a planar cell polarity protein that is involved in ciliogenesis and directional cell movement. Knockout studies in mice exhibit neural tube defects and defective cilia, and mutations in this gene are associated with neural tube defects in humans. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2012]

AP2A1 (HGNC:561): (adaptor related protein complex 2 subunit alpha 1) This gene encodes the alpha 1 adaptin subunit of the adaptor protein 2 (AP-2) complex found in clathrin coated vesicles. The AP-2 complex is a heterotetramer consisting of two large adaptins (alpha or beta), a medium adaptin (mu), and a small adaptin (sigma). The complex is part of the protein coat on the cytoplasmic face of coated vesicles which links clathrin to receptors in vesicles. Alternative splicing of this gene results in two transcript variants encoding two different isoforms. A third transcript variant has been described, but its full length nature has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23424375).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025129.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FUZ	NM_025129.5	MANE Select	c.1060G>T	p.Asp354Tyr	missense	Exon 11 of 11	NP_079405.2
	FUZ	NM_001352262.2		c.1063G>T	p.Asp355Tyr	missense	Exon 11 of 11	NP_001339191.1
	FUZ	NM_001171937.2		c.952G>T	p.Asp318Tyr	missense	Exon 10 of 10	NP_001165408.1	Q9BT04-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FUZ	ENST00000313777.9	TSL:1 MANE Select	c.1060G>T	p.Asp354Tyr	missense	Exon 11 of 11	ENSP00000313309.4	Q9BT04-1
	FUZ	ENST00000881282.1		c.1141G>T	p.Asp381Tyr	missense	Exon 12 of 12	ENSP00000551341.1
	FUZ	ENST00000881283.1		c.1081G>T	p.Asp361Tyr	missense	Exon 11 of 11	ENSP00000551342.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152050 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 249378 AF XY: 0.0000370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461250 Hom.: 0 Cov.: 37 AF XY: 0.0000151 AC XY: 11 AN XY: 726900

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.000224 AC: 10 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111878

Other (OTH) AF: 0.0000497 AC: 3 AN: 60386

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152168 Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3 AN XY: 74384

African (AFR) AF: 0.0000722 AC: 3 AN: 41542

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Neural tube defects, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
PhyloP100		2.0
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.14
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.017	D
Polyphen		0.77	P
Vest4		0.63
MutPred		0.24		Gain of phosphorylation at D354 (P = 0.009)
MVP		0.22
MPC		0.65
ClinPred		0.49	T
GERP RS		3.3
Varity_R		0.15
gMVP		0.48
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs139365610; hg19: chr19-50310605;